Mechanisms underlying the diminished sensitivity to prolactin negative feedback during lactation: Reduced STAT5 signaling and up-regulation of cytokine-inducible SH2 domain-containing protein (CIS) expression in tuberoinfundibular dopaminergic neurons

Hyperprolactinaemia during lactation is a consequence of the sucking stimulus and in part due to reduced prolactin (PRL) negative feedback. To date, the mechanisms involved in this diminished sensitivity to PRL feedback are unknown but may involve changes in PRL signal transduction within tuberoinfundibular dopaminergic (TIDA) neurons. Therefore, we investigated signal transducers and activators of transcription (STAT) 5 signaling in the TIDA neurons of lactating rats. Dual-label confocal immunofluorescence studies were used to determine the intracellular distribution of STAT5 within TIDA neurons in the dorsomedial arcuate nucleus. In lactating rats with pups removed for 16 h, injection of ovine PRL significantly (P < 0.05) increased the STAT5 nuclear/cytoplasmic ratio compared with vehicle-treated mothers. In contrast, ovine PRL injection did not increase the STAT5 nuclear/cytoplasmic ratio in lactating mothers with pups, demonstrating that PRL signal transduction through STAT5 is reduced in TIDA neurons in the presence of pups. To investigate possible mechanisms involved in reduced PRL signaling, we examined the expression of suppressors of cytokine signaling (SOCS) proteins. Northern analysis on whole hypothalamus showed that CIS (cytokine-inducible SH2 domain-containing protein), but not SOCS1 or SOCS3, mRNA expression was significantly (P < 0.01) up-regulated in suckled lactating rats. Semiquantitative RT-PCR on arcuate nucleus micropunches also showed up-regulation of CIS transcripts. Immunofluorescence studies demonstrated that CIS is expressed in all TIDA neurons in the dorsomedial arcuate nucleus, and the intensity of CIS staining in these neurons is significantly (P < 0.05) increased in lactating rats with sucking pups. Together, these results support the hypothesis that loss of sensitivity to PRL-negative feedback during lactation is a result of increased CIS expression in TIDA neurons.

The role of gender in the construction and evaluation of feedback effectiveness

This study investigated factors that influence managers’ conceptions and subordinates’ perceptions of effective feedback. A social rules perspective was used to operationalize male and female managers’ conceptions of effective negative feedback. In the first study, 68 male and female managers identified their optimal strategies for providing feedback to subordinates. Male and female managers endorsed different goals and tactics for giving negative feedback, particularly in terms of levels of participation and directness. In the second study, 116 male and female subordinates evaluated the comparative effectiveness and difficulty of these and other standard approaches to feedback. The female manager strategy was evaluated by both men and women as generally more task and relationship effective but not more difficult to enact.

Bistability and switching in the lysis/lysogeny genetic regulatory network of bacteriophage lambda

Bistability and switching are two important aspects of the genetic regulatory network of phage. Positive and negative feedbacks are key regulatory mechanisms in this network. By the introduction of threshold values, the developmental pathway of A phage is divided into different stages. If the protein level reaches a threshold value, positive or negative feedback will be effective and regulate the process of development. Using this regulatory mechanism, we present a quantitative model to realize bistability and switching of phage based on experimental data. This model gives descriptions of decisive mechanisms for different pathways in induction. A stochastic model is also introduced for describing statistical properties of switching in induction. A stochastic degradation rate is used to represent intrinsic noise in induction for switching the system from the lysogenic pathway to the lysis pathway. The approach in this paper represents an attempt to describe the regulatory mechanism in genetic regulatory network under the influence of intrinsic noise in the framework of continuous models. (C) 2003 Elsevier Ltd. All rights reserved.

T1/ST2 - an IL-1 receptor-like modulator of immune responses

Th2-associated factors such as IL-4 are involved in both the development of Th2 responses (via modulating Th2 cell differentiation) and in the effector phase of Th2 responses (via modulating macrophage activation). The IL-1 receptor-like protein ST2 (T1, Fit-1, or DER4) is expressed as a membrane-bound (ST2L) or secreted form (sST2), and has been clearly implicated as a regulator of both the development and effector phases of Th2-type responses. Here we analyze the mechanisms and therapeutic implications of the unique ability of ST2 to promote development and function of type 2 helper T cells through a positive feedback loop, as well as to act as a negative feedback modulator of macrophage pro-inflammatory function. (C) 2004 Elsevier Ltd. All rights reserved.

The effect of active immunization against adrenocorticotropic hormone on cortisol, beta-endorphin, vocalization, and growth in pigs

Because the poor growth performance of intensively housed pigs is associated with increased circulating glucocorticoid concentrations, we investigated the effects of glucocorticoid suppression by inducing a humoral immune response to ACTH on physiological and production variables in growing pigs. Grower pigs (28.6 0.9 kg) were immunized with amino acids 1 through 24 of ACTH conjugated to ovalbumin and suspended in diethylaminoethyl (DEAE) dextran-adjuvant or adjuvant alone (control) on d 1, 28, and 56. The ACTH-specific antibody titers generated suppressed increases in cortisol concentrations on d 63 in response to an acute stressor (P = 0.002; control = 71 +/- 8.2 ng/ mL; ACTH-immune = 43 +/- 4.9 ng/mL) without altering basal concentrations. Plasma beta-endorphin concentrations were also increased (P < 0.001) on d 63 (control = 18 +/- 2.1 ng/mL; ACTH-immune = 63 +/- 7.3 ng/mL), presumably because of a release from negative feedback on the expression of proopiomelanocortin in pituitary corticotropes. Immunization against ACTH did not alter ADG (P = 0.120; control = 1,077 25; ACTH-immune = 1,143 25 g) or ADFI (P = 0.64; control = 2,719 42; ACTH-immune = 2,749 42 g) and did not modify behavior (P = 0.681) assessed by measuring vocalization in response to acute restraint. In summary, suppression of stress-induced cortisol responses through ACTH immunization increased beta-endorphin concentrations, but it did not modify ADG, ADFI, or restraint vocalization score in growing pigs.